The Houston Center for Acquired Resistance Research (H-CARR)

休斯顿获得性耐药研究中心 (H-CARR)

• 批准号: 10518173
• 负责人: Jeffrey Nicholas Myers
• 金额: $ 123.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518173
• 关键词: Accounting; Acute; Adrenergic Agents; Algorithms; Amino Acids; Biological; Biological Markers; Biomass; Cancer Etiology; Carbon; Cessation of life; Cetuximab; Chronic; Cisplatin; Citric Acid Cycle; Clinical; Clinical Trials; Data; Dependence; Development; Distant Metastasis; Extinction (Psychology); FADH2; GPX2 gene; Generations; Genomics; Genotoxic Stress; Glutathione; Glycolysis; Goals; Gold; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Image; Immune checkpoint inhibitor; Individual; Infrastructure; Invaded; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Medicine; Metabolic; Metabolic stress; Modality; Modeling; Molecular; Mutation; Neoadjuvant Therapy; Neoplasm Circulating Cells; Neoplasm Metastasis; Neurons; Paracrine Communication; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Production; Pyruvate; Regimen; Research; Research Personnel; Resistance; Resistance development; Role; Signal Transduction; Solid Neoplasm; Stress; TP53 gene; Technical Expertise; Testing; Time; Tumor Biology; Tumor Immunity; University of Texas M D Anderson Cancer Center; Upper aerodigestive tract cancer; afferent nerve; base; cancer cell; cancer imaging; cancer survival; chemotherapeutic agent; chemotherapy; clinical application; clinical practice; college; design; early detection biomarkers; experimental study; imaging study; immunogenic; improved; individual patient; insight; metabolic imaging; metabolomics; multidisciplinary; neoplastic cell; non-invasive imaging; novel; precision oncology; prevent; prospective; response; standard of care; targeted agent; transcriptomics; translational potential; tumor; tumor metabolism; tumor-immune system interactions

Overall SUMMARY Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide with ~500,000 cases/year. Cisplatin is the gold standard systemic agent for HNSCC. Cisplatin resistance, both intrinsic and acquired, has been described in preclinical models and is frequently encountered in clinical practice; when it occurs it is deadly. The overarching goal of H-CARR is to develop a robust biological understanding of the key drivers of cisplatin resistance in HNSCC and develop the means of detecting it early in development and overcoming it once it arises. We previously showed that: 1) cellular processing of cisplatin generated metabolic stress is a critical driver of sensitivity and/or resistance and 2) coordinated genomic (TP53 mutation) and transcriptomic (Nrf-2 activation) reprogramming is essential to organizing the metabolic response to cisplatin generated stress. H-CARR brings together our biological and metabolic models of cisplatin resistance and our translational capabilities to image tumor metabolism non-invasively and detect biological shifts using circulating tumor cells (CTCs), to provide a comprehensive window into acquisition of cisplatin resistance as outlined in the Projects listed below, supported by a robust administrative and analytical infrastructure organized into 3 Cores. Project 1 will use state of the art metabolomic studies to identify the critical metabolic dependencies of cisplatin resistant HNSCC, identify opportunities for effective metabolic inhibition and improve our understanding of the cross-talk between the acquisition of cisplatin resistance and modulation of the tumor immune microenvironment. Project 2 will explore the genomic and transcriptomic reprogramming required to sustain the metabolic shifts which accompany development of resistance and interrogate how Nrf-2 dependent and independent signaling drives resistance and enhanced distant metastasis through intrinsic cellular mechanisms and paracrine signaling between tumor cells and adrenergic neurons. Project 3 will test whether the metabolic reprogramming outlined in Project 1 is detectable via non-invasive imaging (hyperpolarized magnetic resonance imaging) and whether the biological shifts outlined in Project 2 due to clonal extinction and expansion can be detected using CTC analysis in patients undergoing cisplatin-based treatment. H-CARR has the potential to realize the full clinical utility of cisplatin by identifying acquisition of resistance early during treatment and developing the means to overcome this and associated phenotypes such as enhanced distant metastasis. Successful completion of the proposed experiments will generate the new clinical standard for precision oncology approaches to clinical utilization of cisplatin in HNSCC and related upper- aerodigestive tract cancers of the lung and esophagus and therefore have a major impact on cancer survival worldwide.

总体汇总 头颈部鳞状细胞癌（HNSCC）仍然是全球癌症死亡的主要原因 约50万例/年。顺铂是HNSCC的金标准全身药物。顺铂耐药，两者 内在的和获得的，已在临床前模型中描述，并且在临床实践中经常遇到; 一旦发生，它是致命的。H-CARR的首要目标是发展一个强大的生物学理解 HNSCC中顺铂耐药的关键驱动因素，并开发在发育早期检测其的方法 一旦出现就克服它我们以前表明：1）顺铂的细胞加工产生 代谢应激是敏感性和/或抗性的关键驱动因素，以及2）协调的基因组（TP 53突变） 转录组（Nrf-2激活）重编程对于组织对顺铂的代谢反应至关重要 产生了压力H-CARR汇集了我们的顺铂耐药生物学和代谢模型， 非侵入性地对肿瘤代谢进行成像并使用循环检测生物转变的翻译能力 肿瘤细胞（CTC），以提供获得顺铂耐药性的全面窗口，如 下面列出的项目，由一个强大的行政和分析基础设施组织成3个核心的支持。 项目1将使用最先进的代谢组学研究，以确定关键的代谢依赖性， 顺铂耐药HNSCC，确定有效代谢抑制的机会，并提高我们的理解 顺铂耐药性的获得和肿瘤免疫调节之间的相互作用 微环境项目2将探索维持基因组和转录组所需的重编程。 代谢变化伴随着抗性的发展，并询问Nrf-2依赖性和 独立信号通过内在细胞机制驱动耐药性和增强的远处转移 以及肿瘤细胞和肾上腺素能神经元之间的旁分泌信号。项目3将测试代谢是否 项目1中概述的重编程可通过非侵入性成像（超极化磁共振）检测 以及项目2中概述的由于克隆灭绝和扩张而引起的生物学变化是否可以 在接受基于顺铂治疗的患者中使用CTC分析检测。 H-CARR有可能通过识别顺铂的获得来实现顺铂的全部临床效用。 在治疗过程中的早期抗性，并开发克服这种抗性和相关表型的方法， 增强的远处转移。成功完成拟议的实验将产生新的 精确肿瘤学方法的临床标准，以确定顺铂在HNSCC和相关上层肿瘤中的临床应用 肺和食道的呼吸消化道癌症，因此对癌症存活率有重大影响 国际吧